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Vol. 57, Issue 1, 75-81, January 2000
CNS Diseases Research (L.W.F., B.S.B., J.P.P., P.A.V.,
B.L.L., P.R.H.), Chemical and Physical Sciences (J.-H.S., A.J.R.,
D.W.R.), Applied Biotechnology (T.C.B., J.R.L., I.A., J.M.H., G.F.H.),
and Department of Safety Assessment (P.C.M.), Cardiovascular Diseases
Research (M.H.C.), The DuPont Pharmaceuticals Research Laboratories,
Experimental Station, Wilmington, Delaware
Dexfenfluramine was approved in the United States for long-term use as
an appetite suppressant until it was reported to be associated with
valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those
observed in carcinoid disease or after long-term exposure to
5-hydroxytryptamine (5-HT)2-preferring ergot drugs
(ergotamine, methysergide). 5-HT2 receptor stimulation is
known to cause fibroblast mitogenesis, which could contribute to this
lesion. To elucidate the mechanism of "fen-phen"-associated
valvular lesions, we examined the interaction of fenfluramine and its
metabolite norfenfluramine with 5-HT2 receptor subtypes and
examined the expression of these receptors in human and porcine heart
valves. Fenfluramine binds weakly to 5-HT2A,
5-HT2B, and 5-HT2C receptors. In contrast,
norfenfluramine exhibited high affinity for 5-HT2B and
5-HT2C receptors and more moderate affinity for
5-HT2A receptors. In cells expressing recombinant 5-HT2B receptors, norfenfluramine potently stimulated the
hydrolysis of inositol phosphates, increased intracellular
Ca2+, and activated the mitogen-activated protein kinase
cascade, the latter of which has been linked to mitogenic actions of
the 5-HT2B receptor. The level of 5-HT2B and
5-HT2A receptor transcripts in heart valves was at least
300-fold higher than the levels of 5-HT2C receptor
transcript, which were barely detectable. We propose that preferential
stimulation of valvular 5-HT2B receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors
(with or without accompanying 5-HT2A receptor activation) may contribute to valvular fibroplasia in humans.
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